New subgroup analyses from the TULIP Phase III clinical trial programme showed Saphnelo (anifrolumab), a first-in-class type I interferon antagonist, in addition to standard therapy, resulted in a greater reduction in systemic lupus erythematosus (SLE) disease activity regardless of disease duration, standard therapy type and prior treatment, compared to standard therapy alone.1,2,3 The data will be presented at ACR Convergence 2021, the annual meeting of the American College of Rheumatology (ACR), from 5 to 9 November 2021.
A post-hoc analysis from the pooled TULIP-1 and -2 Phase III trials showed consistent efficacy of Saphnelo in adult patients with moderate to severe SLE both with recently diagnosed and established disease.1 Treatment with Saphnelo also resulted in a consistent reduction in disease activity, irrespective of standard therapy at baseline, including oral corticosteroids (OCS), antimalarials and/or immunosuppressants.2 Further, Saphnelo provided a consistent benefit across efficacy endpoints over standard therapy alone amongst patients with or without prior biologic exposure.3
SLE is a complex autoimmune condition that can affect any organ, and patients often experience debilitating symptoms, long-term organ damage and poor health-related quality of life.4,5,6,7 Treating lupus can be difficult. It can take months, or even years, to find the right combination of treatment options.8 Despite advances in therapies, the control of disease activity in SLE remains suboptimal.9 Long-term use of OCS, often used as standard therapy to treat lupus symptoms, is associated with organ damage and significant comorbidities.10,11,12
Professor Susan Manzi, Allegheny Health Network, PA, US, said: “We need to evolve how lupus is treated by considering biologics earlier and more routinely in patients with uncontrolled disease, particularly those who are taking high doses of oral corticosteroids, which can be damaging long-term. These new analyses are compelling because they demonstrate anifrolumab can consistently reduce disease activity in a range of patients with moderate to severe disease, regardless of their prior treatment or disease onset.”
Micki Hultquist, Global Franchise Head, Saphnelo, AstraZeneca, said: “These data add to our understanding of Saphnelo’s compelling clinical profile across a range of patients in areas of unmet need. With Saphnelo as the first new treatment in systemic lupus erythematosus approved in over a decade, we’ve advanced the science and are focused on challenging current treatment expectations in this often-debilitating disease.”
Results* from the new pooled analyses of the Phase III TULIP programme at ACR 2021 include:
Study |
Summary |
|---|---|
Anifrolumab Results in Clinical Benefit Regardless of SLE Disease Duration: Post Hoc Analysis of Data From 2 Phase 3 Trials (abstract #: 1741)1
|
· Patients diagnosed within the last two years and those with established disease experienced a similar benefit with Saphnelo (14.4% improvement over standard therapy alone and 17.1%, respectively, as assessed by the BILAG–based Composite Lupus Assessment, or BICLA, at week 52) |
SLE Treatment History and Anifrolumab Efficacy by Baseline Standard Therapies in Patients With SLE from 2 Phase 3 Trials (abstract #: 1739)2 |
· Patients were separated into subgroups depending on which standard therapies they were receiving at baseline: OCS (82.0%), antimalarials (70.2%), and/or immunosuppressants (48.2%), with most patients receiving combinations of two or more types of standard therapy · Saphnelo was associated with consistently higher BICLA response rates than standard of care alone, regardless of the type of baseline standard therapy use |
Efficacy of Anifrolumab in Patients With SLE Previously Treated With Biologics: Post Hoc Analysis of Pooled Data from 2 Phase 3 Trials (abstract #: 1740)3 |
· Biologic-naïve patients in the trials who received Saphnelo saw similar benefits across efficacy endpoints (measures of comprehensive disease activity, OCS taper and flare rate), to those previously treated with other biologics |
*Analyses were descriptive only; no formal hypotheses were tested.
The adverse reactions that occurred more frequently in patients who received Saphnelo in clinical trials included nasopharyngitis, upper respiratory tract infection, bronchitis, infusion-related reactions, herpes zoster and cough.13,14,15
Saphnelo is approved in the US and Japan and is under regulatory review in the EU for the treatment of SLE. A Phase III trial in SLE using subcutaneous delivery has been initiated and additional Phase III trials are planned for lupus nephritis, cutaneous lupus erythematosus and myositis.
Notes
Financial considerations
AstraZeneca acquired global rights to Saphnelo through an exclusive license and collaboration agreement with Medarex, Inc. in 2004. The option for Medarex to co-promote the product expired on its acquisition by Bristol-Myers Squibb (BMS) in 2009. Under the agreement AstraZeneca will pay BMS a low to mid-teens royalty for sales dependent on geography.
Systemic lupus erythematosus
SLE is an autoimmune disease in which the immune system attacks healthy tissue in the body.16 It is a chronic and complex disease with a variety of clinical manifestations that can impact many organs and can cause a range of symptoms including pain, rashes, fatigue, swelling in joints and fevers.11 More than 50% of patients with SLE develop permanent organ damage, caused by the disease or existing treatments, which exacerbates symptoms and increases the risk of mortality.10,17 At least five million people worldwide have a form of lupus.18
TULIP-1, TULIP-2, MUSE
All three trials for Saphnelo (TULIP-1, TULIP-2 and MUSE) were randomised, double-blinded, placebo-controlled trials in adult patients with moderate to severe SLE who were receiving standard therapy. Standard therapy included at least one of the following: OCS, antimalarials and immunosuppressants (methotrexate, azathioprine or mycophenolate mofetil).13,14,15
The pivotal TULIP (Treatment of Uncontrolled Lupus via the Interferon Pathway) Phase III programme included two trials, TULIP-1 and TULIP-2, that evaluated the efficacy and safety of Saphnelo versus placebo.13,14 TULIP-2 demonstrated superiority across multiple efficacy endpoints versus placebo with both arms receiving standard therapy. In the trial, 362 eligible patients were randomised (1:1) and received a fixed-dose intravenous infusion of 300mg Saphnelo or placebo every four weeks. TULIP-2 assessed the effect of Saphnelo in reducing disease activity as measured by the BILAG-Based Composite Lupus Assessment (BICLA) scale.13 In TULIP-1, 457 eligible patients were randomised (1:2:2) and received a fixed-dose intravenous infusion of 150mg Saphnelo, 300mg Saphnelo or placebo every four weeks, in addition to standard therapy. The trial did not meet its primary endpoint based on the SLE Responder Index 4 (SRI4) composite measure.14
The MUSE Phase II trial evaluated the efficacy and safety of two doses of Saphnelo versus placebo. In MUSE, 305 adults were randomised and received a fixed-dose intravenous infusion of 300mg Saphnelo, 1,000mg Saphnelo or placebo every four weeks, in addition to standard therapy, for 48 weeks. The trial showed improvement versus placebo across multiple efficacy endpoints with both arms receiving standard therapy.15
In SLE, along with the pivotal TULIP Phase III programme, Saphnelo continues to be evaluated in a long-term extension Phase III trial and a Phase III trial assessing subcutaneous delivery.19,20 In addition, AstraZeneca is exploring the potential of Saphnelo in a variety of diseases where type I IFN plays a key role, including lupus nephritis, cutaneous lupus erythematosus and myositis.
Post-hoc TULIP subgroup analysis will be presented at ACR 2021: Clinical benefit of anifrolumab regardless of SLE disease duration1
Efficacy endpoint |
Results by disease onset subgroup Saphnelo added to standard therapy versus placebo plus standard therapy (95% CI; nominal p-value) |
|
|
Recent onset (<2 years) |
Established |
BICLA response at Week 52 |
Saphnelo: 47.6% Placebo: 33.2%
∆14.4% (-2.2-31.1; p=0.090) |
Saphnelo: 47.4% Placebo: 30.3%
∆17.1% (9.3-24.8; p<0.001) |
Post-hoc TULIP subgroup analyses will be presented at ACR 2021: SLE treatment history and anifrolumab efficacy by baseline standard therapies2
Baseline therapy subgroup |
BICLA results Saphnelo added to standard therapy versus placebo plus standard therapy (95% CI; nominal p-value) |
Overall |
Saphnelo: 47.5% Placebo: 30.8%
∆16.6% (9.7-23.6; p<0.001) |
OCS only |
Saphnelo: 45.5% Placebo: 23.7%
∆21.8% (2.4-41.2; p=0.028) |
Antimalarial only |
Saphnelo: 43.8% Placebo: 28.9%
∆14.9% (-7.4-37.2; p=0.189) |
Immunosuppressant only |
Saphnelo: 78.4% Placebo: 27.6%
∆50.8% (-0.07-100.0; p=0.053) |
OCS + antimalarial |
Saphnelo: 45.1% Placebo: 33.8%
∆11.3% (-2.0-24.6; p=0.096) |
OCS + immunosuppressant |
Saphnelo: 46.0% Placebo: 28.9%
∆17.1% (-1.4-35.7; p=0.070) |
Antimalarial + immunosuppressant |
Saphnelo: 40.0% Placebo: 33.0%
∆6.9% (-24.0-37.9; p=0.660) |
OCS + antimalarial + immunosuppressant |
Saphnelo: 53.6% Placebo: 32.2%
∆21.4% (7.4-35.4; p=0.003) |
Post-hoc TULIP subgroup analyses will be presented at ACR 2021: Efficacy of anifrolumab in patients with SLE previously treated with biologics3
Efficacy endpoint |
Results by biologic treatment subgroup Saphnelo added to standard therapy versus placebo plus standard therapy (95% CI) |
|
|
Biologic experienced |
Biologic naïve |
BICLA response at Week 52 |
Saphnelo: 44.1% Placebo: 24.6%
∆19.4% (4.2-34.6) |
Saphnelo: 49.1% Placebo: 32.4%
∆16.6% (8.8-24.5) |
SRI(4) response at Week 52 |
Saphnelo: 53.4% Placebo: 28.1%
∆25.3% (9.9-40.7) |
Saphnelo: 52.3% Placebo: 43.2%
∆9.1% (1.0-17.2) |
Sustained OCS reduction at Week 40-52 |
Saphnelo: 52.9% Placebo: 28.2%
∆24.7% (2.0-47.4) |
Saphnelo: 50.0% Placebo: 32.5%
∆17.5% (6.6-28.4) |
Annualised flare rate through Week 52 |
Saphnelo: 0.48 Placebo: 0.74
*0.65 (1.05-0.41) |
Saphnelo: 0.51 Placebo: 0.64
*0.78 (1.02-0.60) |
∆ = treatment difference, percentage points; * = rate ratio
CI: confidence interval
BICLA: British Isles Lupus Assessment Group (BILAG)-based combined lupus assessment
SRI(4): SLE Responder Index
Saphnelo
Saphnelo (anifrolumab) is a fully human monoclonal antibody that binds to subunit 1 of the type I IFN receptor, blocking the activity of type I IFN.14 Type I IFNs such as IFN-alpha, IFN-beta and IFN-kappa are cytokines involved in regulating the inflammatory pathways implicated in SLE.21,22,23,24,25,26 The majority of adults with SLE have increased type I IFN signalling, which is associated with increased disease activity and severity.21,27
AstraZeneca in Respiratory & Immunology
Respiratory & Immunology, part of BioPharmaceuticals, is one of AstraZeneca’s main disease areas and is a key growth driver for the Company.
AstraZeneca is an established leader in respiratory care with a 50-year heritage. The Company aims to transform the treatment of asthma and COPD by focusing on earlier biology-led treatment, eliminating preventable asthma attacks, and removing COPD as a top-three leading cause of death. The Company’s early respiratory research is focused on emerging science involving immune mechanisms, lung damage and abnormal cell-repair processes in disease and neuronal dysfunction.
With common pathways and underlying disease drivers across respiratory and immunology, AstraZeneca is following the science from chronic lung diseases to immunology-driven disease areas. The Company’s growing presence in immunology is focused on five mid- to late-stage franchises with multi-disease potential, in areas including rheumatology (including systemic lupus erythematosus), dermatology, gastroenterology, and systemic eosinophilic-driven diseases. AstraZeneca’s ambition in Respiratory & Immunology is to achieve disease modification and durable remission for millions of patients worldwide.
AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.
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References
1. Kalunian KC, et al. Anifrolumab Results in Favorable Responses Regardless of SLE Disease Duration: Post Hoc Analysis of Data from 2 Phase 3 Trials. Poster presentation at: ACR Convergence 2021; 9 November 2021; virtual. Abstract ID: 1741.
2. Manzi S, et al. SLE Treatment History and Anifrolumab Efficacy by Baseline Standard Therapies in Patients with SLE from 2 Phase 3 Trials. Poster presentation at: ACR Convergence 2021; 9 November 2021; virtual. Abstract ID: 1739.
3. Furie R, et al. Efficacy of Anifrolumab in Patients with SLE Previously Treated with Biologics: Post Hoc Analysis of Data from 2 Phase 3 Trials. Poster presentation at: ACR Convergence 2021; 9 November 2021; virtual. Abstract ID: 1740.
4. Centers for Disease Control and Prevention. Systemic Lupus Erythematosus (SLE). Available online. Accessed November 2021.
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11. Scientific data on file.
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15. Furie R, et al. Anifrolumab, an Anti–Interferon‐α Receptor Monoclonal Antibody, in Moderate‐to‐Severe Systemic Lupus Erythematosus. Arthritis Rheumatol. 2017;69(2):376-386. Accessed November 2021.
16. The Lupus Foundation of America. What is Lupus? Available online. Accessed November 2021.
17. Segura BT, et al. Damage accrual and mortality over long-term follow-up in 300 patients with systemic lupus erythematosus in a multi-ethnic British cohort. Rheumatol. 2020;59(3):524-533. Accessed November 2021.
18. The Lupus Foundation of America. Lupus facts and statistics. Available online. Accessed November 2021.
19. ClinicalTrials.gov. Long Term Safety of Anifrolumab in Adult Subjects With Active Systemic Lupus Erythematosus (TULIP SLE LTE). NCT Identifier: NCT02794285. Accessed November 2021.
20. ClinicalTrials.gov. Subcutaneous Anifrolumab in Adult Patients With Systemic Lupus Erythematosus (Tulip SC). NCT Identifier: NCT04877691. Accessed November 2021.
21. Lauwerys BR, et al. Type I interferon blockade in systemic lupus erythematosus: where do we stand? Rheumatol. 2014;53:1369-1376. Accessed November 2021.
22. Sarkar MK, et al. Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa. Ann Rheum Dis. 2018;77:1653-1664. Accessed November 2021.
23. Jefferies CA. Regulating IRFs in IFN Driven Disease. Front Immunol. 2019;10:325. Accessed November 2021.
24. Mai L, et al. The baseline interferon signature predicts disease severity over the subsequent 5 years in systemic lupus erythematosus. Arthritis Res Ther. 2021;23:29. Accessed November 2021.
25. López de Padilla CM, et al. The Type I Interferons: Basic Concepts and Clinical Relevance in Immune-mediated Inflammatory Diseases. Gene. 2016;576(101):14-21. Accessed November 2021.
26. Rönnblom L, et al. Interferon pathway in SLE: one key to unlocking the mystery of the disease. Lupus Sci Med. 2019;6(1):e000270. Accessed November 2021.
27. Crow MK. Type I Interferon in the Pathogenesis of Lupus. J Immunol. 2014;192(12):5459-5468. Accessed November 2021.
Veeva ID: Z4-38947
Date of Preparation: October 2021